Eprenetapopt Plus Azacitidine in <i>TP53</i>-Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myélodysplasies (GFM)

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PURPOSE

TP53-mutated ( TP53m) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have very poor outcome irrespective of the treatment received, including 40% responses (20% complete remission [CR]) with azacitidine (AZA) alone, short response duration, and a median overall survival (OS) of approximately 6 months. Eprenetapopt (APR-246), a novel first-in-class drug, leads to p53 protein reconformation and reactivates its proapoptotic and cell-cycle arrest functions.

PATIENTS AND METHODS

This phase II study assessed the safety and efficacy of eprenetapopt in combination with AZA in untreated high or very high International Prognostic Scoring System-R TP53m MDS and AML patients.

RESULTS

Fifty-two TP53m patients (34 MDS, 18 AML [including seven with more than 30% blasts]) were enrolled. In MDS, we observed an overall response rate (ORR) of 62%, including 47% CR, with a median duration of response at 10.4 months. In AML, the ORR was 33% including 17% CR (27% and 0% CR in AML with less than and more than 30% marrow blasts, respectively). Seventy-three percent of responders achieved TP53 next-generation sequencing negativity (ie, variant allele frequency < 5%). The main treatment-related adverse events were febrile neutropenia (36%) and neurologic adverse events (40%), the latter correlating with a lower glomerular filtration rate at treatment onset ( P < .01) and higher age ( P = .05), and resolving with temporary drug interruption without recurrence after adequate eprenetapopt dose reduction. With a median follow-up of 9.7 months, median OS was 12.1 months in MDS, and 13.9 and 3.0 months in AML with less than and more than 30% marrow blasts, respectively.

CONCLUSION

In this very high-risk population of TP53m MDS and AML patients, eprenetapopt combined with AZA was safe and showed potentially higher ORR and CR rate, and longer OS than reported with AZA alone.

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Most cited references 23

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The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease.

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Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia

Courtney D DiNardo, Brian Jonas, Vinod Pullarkat … (2020)

Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study.

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Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.

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Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens. In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m(2) per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French-American-British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799. Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21.1 months (IQR 15.1-26.9), median overall survival was 24.5 months (9.9-not reached) for the azacitidine group versus 15.0 months (5.6-24.1) for the conventional care group (hazard ratio 0.58; 95% CI 0.43-0.77; stratified log-rank p=0.0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50.8% (95% CI 42.1-58.8) of patients in the azacitidine group were alive compared with 26.2% (18.7-34.3) in the conventional care group (p<0.0001). Peripheral cytopenias were the most common grade 3-4 adverse events for all treatments. Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.

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Author and article information

Journal

Journal ID (nlm-ta): J Clin Oncol

Journal ID (iso-abbrev): J Clin Oncol

Journal ID (hwp): jco

Journal ID (pmc): jco

Journal ID (publisher-id): JCO

Title: Journal of Clinical Oncology

Publisher: Wolters Kluwer Health

ISSN (Print): 0732-183X

ISSN (Electronic): 1527-7755

Publication date (Print): 10 May 2021

Publication date (Electronic): 18 February 2021

Volume: 39

Issue: 14

Pages: 1575-1583

Affiliations

[ ¹ ]Cote d'Azur University, Hematology Department, Centre Hospitalier Universitaire of Nice, Nice, France

[ ² ]Cote d'Azur University, Mediterranean Center of Molecular Medicine, INSERM U1065, Nice, France

[ ³ ]GFM

[ ⁴ ]Hematology Department, Hospital Saint Louis, Assistance Publique des Hopitaux de Paris (APHP), and Paris University, Paris, France

[ ⁵ ]Neurology Department, Hospital Saint Louis, APHP, Paris, France

[ ⁶ ]Pharmacy Department, Hospital Saint Louis, APHP, Paris, France

[ ⁷ ]Hematology Department, CHU of Nantes, Nantes, France

[ ⁸ ]Hematology Department, IUCT Oncopôle, Toulouse, France

[ ⁹ ]Hematology Department, Centre Henri Becquerel, Rouen, France

[ ¹⁰ ]Hematology Department, Hospital Cochin, APHP, Paris, France

[ ¹¹ ]Hematology Department, CHU of Lille, Lille, France

[ ¹² ]Hematology Unit, Moffitt Cancer Center and Research Institute, Tampa, FL

[ ¹³ ]SBIM, Hospital Saint Louis, APHP, and Paris University, Paris, France

[ ¹⁴ ]Molecular Oncology Unit, Hospital Saint Louis, APHP, and Paris University, Paris, France

Author notes

Pierre Fenaux, MD, PhD, Assistance Publique—Hôpitaux de Paris, Hôpital Saint Louis, Service d'hématologie sénior, 1 Avenue Claude Vellefaux, 75475 Paris, and Paris University, Paris, France; e-mail: pierre.fenaux@ 123456aphp.fr .